This invention relates to chemical compounds having pharmacological activity, to pharmaceutical compositions which include these compounds, and to a pharmaceutical method of treatment. More particularly, this invention concerns certain malonamide esters, compounds which inhibit the enzyme acylcoenzyme A:cholesterol acyltransferase (ACAT), pharmaceutical compositions containing these compounds, and a method of treating hypercholesterolemia and atherosclerosis.
In recent years the role which elevated blood plasma levels of cholesterol play in pathological conditions in man has received much attention. Deposits of cholesterol in the vascular system have been indicated as causative of a variety of pathological conditions including coronary heart disease.
Initially, studies of this problem were directed toward finding therapeutic agents which would be effective in lowering total serum cholesterol levels. It is now known that cholesterol is transported in the blood in the form of complex particles consisting of a core of cholesteryl esters plus triglycerides and an exterior consisting primarily of phospholipids and a variety of types of protein which are recognized by specific receptors. For example, cholesterol is carried to the sites of deposit in blood vessels in the form of low density lipoprotein cholesterol (LDL cholesterol) and away from such sites of deposit by high density lipoprotein cholesterol (HDL cholesterol).
Following these discoveries, the search for therapeutic agents which control serum cholesterol turned to finding compounds which are more selective in their action; that is, agents which are effective in elevating the blood serum levels of HDL cholesterol and/or lowering the levels of LDL cholesterol. While such agents are effective in moderating the levels of serum cholesterol, they have little or no effect on controlling the initial absorption of dietary cholesterol in the body through the intestinal wall.
In intestinal mucosal cells, dietary cholesterol is absorbed as free cholesterol which must be esterified by the action of the enzyme acyl-CoA: cholesterol acyltransferase (ACAT) before it can be packaged into the chylomicrons which are then released into the blood stream. Thus, therapeutic agents which effectively inhibit the action of ACAT prevent the intestinal absorption of dietary cholesterol into the blood stream or the reabsorption of cholesterol which has been previously released into the intestine through the body's own regulatory action.
U.S. Ser. No. 508,315, filed Apr. 11, 1990, now abandoned, and U.S. Ser. No. 667,813 filed Mar. 15, 1991, now abandoned, and related Patent Cooperation Treaty Application PCT/US91/02441 filed Apr. 9, 1991, and published as WO91/15464 on Oct. 17, 1991, disclose amide ester ACAT inhibitors of the following formula: ##STR2## wherein each of m and n is independently 0, 1, or 2, wherein X is oxygen or sulfur;
wherein each of R.sub.1 and R.sub.2 is independently
(a) hydrogen, PA1 (b) the group ##STR3## wherein t is 0 or 1 to 4; w is 0 or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R.sub.8 and R.sub.9 are independently selected from hydrogen or an alkyl group having from 1 to 6 carbon atoms; R.sub.10 is phenyl, phenyl substituted with from 1 to 3 substituents selected from straight or branched alkyl having from 1 to 6 carbon atoms and which is straight or branched, straight or branched alkoxy having from 1 to 6 carbon atoms and which is straight or branched, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, --COOH, --COOalkyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, or --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p is 0 or 1 and each of R.sub.6 and R.sub.7 is independently selected from hydrogen or an alkyl group having from 1 to 4 carbon atoms, or R.sub.10 is a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 nitrogen, oxygen or sulfur atoms in at least 1 ring member; or when R.sub.8 is hydrogen each of R.sub.9 and R.sub.10 is independently selected from phenyl, phenyl substituted with from 1 to 3 substituents selected from straight or branched alkyl having from 1 to 6 carbon atoms and which is straight or branched, straight or branched alkoxy having from 1 to 6 carbon atoms and which is straight or branched, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, --COOH, --COOalkyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, or --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein R.sub.6, R.sub.7, and p have the meanings defined above, or a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 nitrogen, oxygen, or sulfur atoms in at least 1 ring member; PA1 (d) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and which is saturated or contains from 1 to 3 double bonds; PA1 (e) an alkyl group having from 1 to 6 carbon atoms wherein the terminal carbon is substituted with hydroxy or --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 have the meanings defined hereinabove; PA1 (f) a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 nitrogen, oxygen or sulfur atoms in at least 1 ring member; PA1 (g) phenyl or phenyl substituted with from 1 to 3 substituents selected from phenyl, PA1 (h) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from PA1 (i) NR.sub.1 R.sub.2 taken together form a monocyclic heterocyclic group selected from pyrrolidono, piperidino, morpholino, or piperazino, each of which is unsubstituted or is substituted with 1 substituent selected from phenyl, straight or branched alkyl having from 1 to 6 carbon atoms or .omega.-hydroxyalkyl having from 1 to 6 carbon atoms; PA1 (a) hydrogen; PA1 (b) a straight or branched alkyl group having from 1 to 10 carbon atoms; PA1 (c) a straight chain alkyl group having from 1 to 10 carbon atoms wherein the terminal carbon atom is substituted with hydroxy or NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 have the meanings defined above; PA1 (a) hydrogen, PA1 (b) phenyl which is unsubstituted or is substituted with from 1 to 3 substituents selected from: PA1 (c) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from PA1 (e) the group ##STR6## wherein q, r, s, and Ar' have the meanings defined above; (f) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and which is saturated or contains from 1 to 3 double bonds; or PA1 (g) a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 nitrogen, oxygen or sulfur atoms in at least 1 ring member; PA1 (b) 1- or 2-naphthyl which is substituted with from 2 to 3 substituents selected from PA1 (c) ##STR10## wherein R.sub.11, R.sub.12, and R.sub.13 are each independently (a) hydrogen, PA1 (b) alkyl of from 1 to 4 carbon atoms and which is straight or branched; PA1 (c) alkoxy of from 1 to 3 carbon atoms and which is straight or branched; PA1 (d) alkylthio of from 1 to 3 carbon atoms and which is straight or branched; PA1 (e) fluorine; PA1 (f) chlorine; PA1 (g) bromine; PA1 (a) phenyl, phenyl substituted with from 1 to 3 substituents selected from straight or branched chain alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 4 carbon atoms, straight or branched alkylthio having from 1 to 4 carbon atoms, F, Cl, Br, CF.sub.3, CN, NO.sub.2, phenyl, cycloalkyl of from 3 to 8 carbon atoms; PA1 (b) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from straight or branched alkyl having from 1 to 4 carbon atoms, straight or branched alkoxy having from 1 to 3 carbon atoms; PA1 (c) hydrogen; PA1 (d) fluorine; PA1 (e) straight or branched chain alkyl having from 1 to 4 carbon atoms; PA1 (f) a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 nitrogen, oxygen, or sulfur atoms in at least 1 ring member; PA1 (g) hydroxy; and PA1 (h) --(CH.sub.2).sub.y NR'R" wherein y has the same meaning as above and each of R' and R" is independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl, cycloalkyl of from 5 to 8 carbon atoms, or where R' and R" taken together also represent ##STR11## wherein m and n are each an integer of from 2 to 3 and B is a direct bond, or oxygen, sulfur; with the proviso that R.sub.14 and R.sub.15 are not both hydrogen, fluorine, or a straight or branched chain alkyl or a combination thereof; PA1 (a) hydrogen, PA1 (b) phenyl which is unsubstituted or is substituted with from 1 to 3 substituents selected from: PA1 (c) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from PA1 (d) the group ##STR12## wherein t is 0 or 1 to 4; w is 0 or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R.sub.28 and R.sub.29 are independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when R.sub.28 is hydrogen, R.sub.29 can be the same as R.sub.30 ; and R.sub.30 is phenyl or phenyl substituted with from 1 to 3 substituents selected from straight or branched alkyl having from 1 to 6 carbon atoms, straight or branched alkoxy having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, --COOH, COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, or --(CH.sub.2).sub.y NR.sub.17 R.sub.18 wherein y, R.sub.17, and R.sub.18 have the meanings defined above; PA1 (e) the group ##STR13## wherein q is 0 or 1 to 3; r is 0, 1, or 2; s is 2 to 6; and Ar.sup.1 is phenyl, PA1 (f) a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and which is saturated or contains from 1 to 3 double bonds; or PA1 (g) a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing at least 1 to 4 nitrogen, oxygen or sulfur atoms in at least 1 ring member;
(c) the group ##STR4## wherein q is 0 or 1 to 3; r is 0, 1, or 2; s is 2 to 6; and Ar' is phenyl, 1- or 2-naphthyl,
phenyl or 1- or 2-naphthyl substituted with alkyl of from 1 to 6 carbon atoms and which is straight or branched, PA0 alkoxy of from 1 to 6 carbon atoms and which is straight or branched, PA0 hydroxy, PA0 benzyloxy, PA0 fluorine, PA0 chlorine, PA0 bromine, PA0 nitro, PA0 trifluoromethyl, PA0 --NH--COCH.sub.3, PA0 --CONH.sub.2, PA0 --COOH, PA0 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched, PA0 --CH.sub.2 COOH, PA0 --CH.sub.2 CONH.sub.2, PA0 --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p, R.sub.6, and R.sub.7 have the meanings defined above;
alkyl having from 1 to 6 carbon atoms and which is straight or branched, PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 phenoxy, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, or PA2 --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p, R.sub.6, and R.sub.7 have the meanings defined above; PA2 phenyl, PA2 alkyl having from 1 to 6 carbon atoms and which is straight or branched, PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched, PA2 --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p, R.sub.6, and R.sub.7 have the meanings defined above; or PA2 phenyl, PA2 alkyl having from 1 to 6 carbon atoms and which is straight or branched, PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 phenoxy, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched, PA2 --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p, R.sub.6, and R.sub.7 have the meanings defined above; PA2 phenyl, PA2 alkyl having from 1 to 6 carbon atoms and which is straight or branched; PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, PA2 --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p, R.sub.6, and R.sub.7 have the meanings defined above; ##STR5## wherein t is 0 or 1 to 4; w is 0 or 1 to 4 with the proviso that the sum of t and w is not greater than 5; R.sub.8 and R.sub.9 are independently selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when R.sub.8 is hydrogen, R.sub.9 can be the same as R.sub.10 ; and R.sub.10 is phenyl or phenyl substituted with from 1 to 3 substituents selected from straight or branched alkyl having from 1 to 6 carbon atoms, straight or branched alkoxy having from 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, --COOH, COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, or --(CH.sub.2).sub.p NR.sub.6 R.sub.7 wherein p, R.sub.6, and R.sub.7 have the meanings defined above; PA2 phenoxy, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, or PA2 --(CH.sub.2).sub.y NR.sub.17 R.sub.18 wherein y is 0 or 1 and each of R.sub.17 and R.sub.18 is independently selected from hydrogen or an alkyl group having from 1 to 4 carbon atoms; PA2 phenyl, PA2 alkyl having from 1 to 6 carbon atoms and which is straight or branched, PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched, PA2 --(CH.sub.2)yNR17R18 wherein y, R17, and R18 have the meanings defined above; or; PA2 phenyl, PA2 alkyl having from 1 to 6 carbon atoms and which is straight or branched, PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 phenoxy, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched, PA2 --(CH.sub.2).sub.y NR.sub.17 R.sub.18 wherein y, R.sub.17, and R.sub.18 have the meanings defined above; PA2 phenyl, PA2 alkyl having from 1 to 6 carbon atoms and which is straight or branched; PA2 alkoxy having from 1 to 6 carbon atoms and which is straight or branched, PA2 hydroxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and is straight or branched, PA2 --(CH.sub.2).sub.y NR.sub.17 R.sub.18 wherein y, R.sub.17, and R.sub.18 have the meanings defined above; PA2 1- or 2-naphthyl, PA2 phenyl or 1- or 2-naphthyl substituted with alkyl of from 1 to 6 carbon atoms and which is straight or branched, PA2 alkoxy of from 1 to 6 carbon atoms and which is straight or branched, PA2 hydroxy, PA2 benzyloxy, PA2 fluorine, PA2 chlorine, PA2 bromine, PA2 nitro, PA2 trifluoromethyl, PA2 --NH--COCH.sub.3, PA2 --CONH.sub.2, PA2 --COOH, PA2 --COOalkyl wherein alkyl has from 1 to 4 carbon atoms and which is straight or branched, PA2 --CH.sub.2 COOH, PA2 --CH.sub.2 CONH.sub.2, PA2 --(CH.sub.2).sub.y NR.sub.17 R.sub.18 wherein y, R.sub.17, and R.sub.18 have the meanings defined above;
wherein each of R.sub.3 and R.sub.4 is independently
wherein R.sub.5 is
with the provisos that (1) when each R.sub.1 and R.sub.2 is the group (b) R.sub.9 is hydrogen or alkyl having from 1 to 6 carbon atoms, and (2) when 1 of R.sub.1 and R.sub.2 is the group (c) the other of R.sub.1 and R.sub.2 is other than (b), (f), or (i); N-oxides thereof, or a pharmaceutically acceptable salt thereof.
U.S. Pat. No. 5,079,137, issued Jan. 7, 1992, to Taguchi, et al., discloses heat-developable color photographic light-sensitive material capable of giving positive color images having high maximum density, low minimum density, and less strain comprising at least a light-sensitive silver halide, a binder, a dye-providing nondiffusible compound capable of releasing a diffusible dye on being reduced, and reducing agent, wherein the light-sensitive material further contains at least one compound represented by the following formula: ##STR7## wherein R.sup.1 and R.sup.2 each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, with a proviso that R.sup.1 and R.sup.2 each represents a group having no redox activity after its cleavage and R.sup.3 and R.sup.4 each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group.
U.S. Pat. No. 5,123,951, issued Jun. 23, 1992, to See, et al., discloses synergistic plant growth regulator compositions containing (i) an ethylene response or ethylene-type response inducing agent and (ii) a malonic acid derivative compound having the formula: ##STR8## wherein R.sub.1, R.sub.2, Y.sub.1, Y.sub.3, Y.sub.4, Y.sub.5, and Y.sub.6 are as defined hereinafter, and in which the amount of compound (ii) used with agent (i) results in a mixture having a greater plant growth regulating effect than the sum total plant growth regulating effect of agent (i) and compound (ii) used alone.
The alpha-aryl or heteroaryl-substituted amide ester ACAT inhibitors of the present invention are not taught by these references. Moreover, the alpha-aryl or heteroaryl-substituted amide ester ACAT inhibitors of the present invention have been found to be characterized as nontoxic in in vivo studies. The nontoxic nature of the compounds of the present invention is particularly advantageous, and will be demonstrated below.